Synthesis of ethers of vitamin a



Patented Dec. 10, 1946 UNITED STATES PATENT 0FFICE SYNTHESIS OF ETHERS OF VITAMIN A Nicholas A. Milas, Belmont, Mass., assignor to Research Corporation, New York, N. Y., a corporation of New York No Drawing. Application January 17, 1945,

Serial No. 573,313

12 Claims. (Cl. 260611) 1 o 2 An object of the present invention is to provide etc, including substituted alkyls such as tria new method for the synthesis of ethers of vitaphenyl methyl in 'which the Rs are phenyl min A. This application is a continuation-inpart of my application Serial No. 409,314, filed September 2, 1941. In the said application I disclosed several methods for the synthesis of ethers of vitamin A based upon the concept of starting with the aldehyde compound CH CH3 CH3 H CH=CH-H-CHO H I CH:

Compoundl and the ketone compound CH; O='J-CH2CHzOC R Compound II R in which R stands for hydrogen or a hydrocarbon group. The group may be any alkyl group such as methyl, ethyl, 30

groups. According to said application, the carbinol of one of said compounds is formed, united with the other compound via the Grignard or metallo derivative thereof, the product hydrogenated to convert the acetylene bond into an ethylene bond and the components dehydrated either before or after their combination. 7

The present application is concerned with the method in which the carbinol of Compound II is dehydrated before being combined with Compound I. Y

The principal steps involvedin this process, starting with Compounds I and II, are as follows:

Compound II is converted into the corresponding acetylene carbinol which is dehydrated and the dehydrated product converted tothe 'corresponding Grignard or metallo derivative (metal of the first group of the periodic system),fthe latter is then reacted with Compound I to form Compound VI which is converted to the vitamin Aether by two routes: (1) it is partially and selectivelyhydrogenated (acetylene to olefin) and the carbinol formed dehydrated or dehydrohalogenated to the vitamin A ether; (2) it is directly dehydrated to the polyen-yne (Compound VII) which is partially and selectively hydrogenated to the vitamin A ether.

The following equations illustrate the process:

om R on, HCECH V (1: R-CO--CHs-CHn- =0 V R-C-O-CHr-CHr- CECH No or Li in R 1 liquid NH; R H 2 Compound II Compound III B CH; t dehydrated CompoundIII R-C-O-CHz-CH: CECB i p-toluene sullonio I acid or AlPOl R Compound IV Compound IV liquid NH; R

Compound V 3 in which X stands for the Grlgnard group or a metal of the first group.

CHC

: H1 Cm Compound V Compound I ------i H l H on:

CHI

Compound VI Compound VII CH; CH]

Compound VI hydrogenation H I H CH:

Compound VIII dehydration -u H Compound VII hydrogenation In the following specific examples of procedures for carrying out the reactions outlined above, the preparation of the ethyl ether of vitamin A will be used as illustrative and the compounds will be referred to by the numbers used in the above equations with the additional designation ethyl.

Preparation of 3-methyl 5-ethozy penta-1-yn 3; 1 (Compound III-ethyl) from ,B-ethoryethyl methyl ketone (Compound II-ethyl) .-0ne liter of liquid ammonia was saturated with dry acetylene and, while stirring and passing acetylene through the liquid, 3.9 g. of lithium (sodium has also been used with less satisfactory results) was added in the course of one-half hour keeping the temperature of the mixture below -40 C. When all of the lithium had been converted to lithium acetylide, the mixture was cooled .to -'70 and to it added slowly with stirring in the course of one hour 58 g. of fl-ethoxy-ethyl methyl ketone. Stirring was continued at the above temperature for 7-8 hours longer while a gentle stream of acetylene was allowed to pass through the mixture. The ammonia was then allowed to evaporate and 250 cc. of other added to the residue and the mixture cooled to 0 and hydrolyzed with a. solution of ammonium sulfate or chloride. The nonaqueous layer was then removed and the aqueous layer extracted twice with 250 cc. of ether and the ether extracts combined, dried and fractionated under reduced pressure using a six-inch Vigreux column. The fraction (28 g.) boiling at 50-51 (4 mm.) was collected and analyzed. 12 1.4370; (14, 0.922.

Anal. calcd. for Cal-11402: C, 67.60; H, 9.86; unsaturation, 2F; active hydrogen (Zerewitinofi), 2. Found: C, 67.59, 67.83; H, 9.44, 9.55; unsaturatlon, 2.1F. (Pd); active hydrogen (Zen), 1.9, 2.06.

This acetylene carbinol gives a heavy precipitate with ammoniacal alcoholic silver nitrate solution.

Compound VIII Vitamin A ether Dehydration of 3-methyl 5-ethoxy lpenta-I-yn- 3-ol (Compound-III-ethyl) to 3-meth1 l S-ethoary penta-3-en-yne-1 (Compound III-ethyl).- Twenty-six grams of 3-methy15-ethoxy penta-lyn-3-ol was passed upwards under a reduced nitrogen pressure (35 mm.) through a tube containing a mixture of aluminum phosphate and pumice and maintained at temperatures between 290-300 C. The crude dehydrated mixture was dried and fractionated under reduced pressure and the fraction boiling at 53-54 (18 mm.) collected and analyzed. It was found to have an active hydrogen (Zen) of 1.01, 0.92 and an unsaturation of 3.1, 3.09F agreeing very well with the theoretical values of 1.0 and 3.0 respectively; n 1.4470.

3-methyl 5-ethoxy penta-1-yn-3-ol can also be dehydrated with anhydrous p-toluene sulfonic acid (usually about one-tenth by weight of the amount of the acetylene carbinol used) in solution with benzene, toluene or Xylene. A portion of the solvent is distilled under a slightly reduced nitrogen pressure carrying with it the water formed by the dehydration of the carbinol. Finally, the mixture was extracted with dilute alkali to remove the p-toluene sulfonic acid, dried and fractionated to recover Compound IV----ethyl.

Conversion of 3-methyl 5-ethozrzpenta-J-enyne-I (Compound IV-ethyl) into its (munard derivative thereof (Compound J--ttyt).---A Grignard reagent was prepared n the usual man ner from 6.3 g. of ethyl bromide and 1.4 g of magnesium. The mixture was then cooled to 0 in an atmosphere of nitrogen and to it was added dropwise with stirring 6.5 g. of B-methyl 5-ethoxy penta-3-en-yne-l, and stirring was continued overnight at room temperature. A white precipitate which was formed in the cold goes slowly into solution at room temperature. Finally, to insure complete reaction, .the mixture was refluxed for one hour before proceeding with the next step.

Reaction of Compound VethyZ with Compound I to form Compound 'VI-ethyl.--'I'he Grignard (Compound Vethyl) described in the previous section was cooled to and to itvadded dropwise with stirring in the course of one-half hour 10.8 g. of Compound I in 50 cc. of-an'hydrous ether. Stirring of the mixture in nitrogen was continued overnight then it was refluxed gently for one hour. Finally, the mixture was cooled to 0 and hydrolyzed with 100 .cc. of water containing g. of ammonium chloride. The ether layer was separated, dried and the ether removed.

The residue was taken up in petroleum ether in order to remove inorganic and other insoluble materials. The petroleum ether was removed and the residue subjected for one hour at 100 C. to a high vacuum --10 mm.) to remove volatile materials such as unreacted portions of- Compounds I andIV. The final product (10.5 g.) is a pale yellow highly viscous liquid and attempts to crystallize it were unsuccessful.

The ultra-violet spectrum of this product shows an absorption band with a maximum at 2330 A having an 1cm. value of 615.

Anal. calcd. for C22H3402; C, 80.00; H, 10.30; unsaturation, 5F; active hydrogen (Zer.), 1.0. Found: C, 79.98, 79.04, 79.65; H, 11.23, 10.54, 11.20; unsaturation, 5.31 (Pt), 5.30 (Pd) F; active hydrogen (Zer.), 1.15.

The slightly higher value for unsaturation is probably due to slow hydrogenolysis of the hydroxyl group.

- Dehydration of Compound VI-ethyl to Compound VII-ethyl.To 250 cc. of pure toluene was added 0.3 g. of p-toluene sulfonic acid monohydrate. To dehydrate the p-toluene sulfonic acid, 100 cc. of toluene was distilled carrying the water with it. The solution was then cooled in nitrogen and to it was added 9.5 g. of Compound VI in 250 cc. of toluene and about 150 cc. of

toluene was distilled in nitrogen. The mixture was then cooled to room temperature and shaken with 150 cc. of, methanol containing v3 g. of potassium hydroxide. Water was then added to separate the alcohol from the toluene layer, the latter removed, dried and the toluene removed under reduced pressure. The residue was further purified first from olefin-free petroleum ether then dissolved in 90% methanol and extracted with petroleum ether and finally fractionated successively in 10 interval from 0 to -78 using anhydrous methanol as solvent. Thus purified, Compound VII-ethyl is almost insoluble in methanol at 40 to -70 C. The final product is a pale yellow highly viscous liquid which exhibits a broad absorption band with a sharp maximum at 3170A having an (10- -40" mm.) and the product boiling at 95-98 collected and analyzed. This has an (3150) value of 1231.

Anal. calcd. for CnHszO: C, 84.61; H, 10.23; unsaturation, 6.0 F; active hydrogen (Zer.) 0.0. Found: C, 84.58, 85.22; H, 10.90, 11.00; unsaturation, 6.39 (Pt), 6.28 (Pd) F; active hydrogen (Zer.), 0.05 (within exptl. error).

Conversion of Compound VII-ethyl into vitamin A ethyl ether.-It is well known that in the partial hydrogenation of an acetylene bond attached to two difierent groups, as in the case of Compound VII, to give the corresponding olefin, the latter may be present in two different isomers, cis and trans. The proportion of these two isomers depends upon the method used to add the two hydrogen atoms to the acetylene bond. For instance, if selective catalytic hydrogenation is employed the predominant isomer present is cis, whereas if a chemical method (e. g. a metal or its amalgam of the first and second groups of the periodic system+alcohol, liquid ammonia or any substance whichgives nascent hydrogen on reacting with the metal, .zinc aluminum or their amalgams or certain alloys of these metals are allowed to react with inorganic or organic bases or organic acids to give nascent hydrogen) is used the predominant isomer present is trans. Examples of each of these two methods are given in the following disclosures:

(1) Catalytic method.To 50 cc. of absolute alcohol was added 0.3398 g. of 10% paladium hydroxide on calcium carbonateand the palladium hydroxide reduced with hydrogen gas into palladium black. To this mixture was then added 1.6505 of compound VII in 25 cc. of absolute alcohol and hydrogen gas was-introduced until 127 cc. (N. T. P.) was absorbed. The reaction was stopped and the vitamin A ether recovered and examinedspectroscopically. The crude product was found to exhibit a broad absorption band in the ultra-violet with a maximum at 3140-3150 A having an value of about 1000. When tested on vitamin A deficient rats this product was found to be biologically very active.

(2) Chemical method.Compound VII (2.031 g.) dissolved in 26 cc. of anhydrous methanol was added to 100 cc. of ethandi containing 6 g. of solid potassium hydroxide and to this mixture was added 0.52 g. of zinc dust. Gentle stirring was provided by nitrogen bubbling through the mixture for seventeen hours. The reaction mixture was then diluted with water and extracted with olefin-free petroleum ether, the latter dried, filtered and the petroleum ether removed. The residue was then examined spectroscopically. It was found to exhibit an absorption band in the ultra-violet with a maximum at 3200 A. The band was not only shifted toward the visible region of the spectrum but it was much narrower than that shown by either the original-dehydro-ether or. the product (cis) made by the first method. That it was partially and selectively hydrogenated, was also shown by a, complete catalytic hydrogenation which gave a value of 4.84 (Pt.) F as compared to 6.2 F found for the original product.

This partial reduction was also accomplished by using an organic acid (acetic acid) in alcoholic solution with zinc dust instead of alkali.

Conversion of Compound VI-ethyl into S-cz's- Compound VIII-ethyl (catalytic method) .-To

100 cc. of absolute alcohol was added about 0.6 g. of 10% paladium hydroxide on calcium carbonate and the palladium hydroxide reduced with hydrogen gas into paladium black. To this mixture was then added 3.3 g. of Compound VI-ethyl in 50 cc. of absolute alcohol and hydrogen gas introduced until about 225 cc. (N. T. P.) was absorbed. The reaction was stopped and the product (Compound VIII-ethyl) recovered as a pale, yellow, highly viscous liquid.

5-cis-Compound VIIIethyl was dehydrated to the 5-cis vitamin A ethyl ether in boiling toluene with small amounts (2% of the weight of Compound VIII-ethyl) of p-toluene sulfonic acid.

In the conversion of 5-cis Compound VIII- etbyl into the 5-cis vitamin A ethyl ether, one may use the following procedure: Dissolve 0.2 of a mole of 5-cis-Compound VIIIethyl in about 150 cc. of anhydrous toluene and add to the mixture 30 g. of anhydrous pyridine. Cool the mixture to between and C. and add with rapid stirring 0.42 of a mole of phosphorus tribromide. Allow the mixture to warm slowly to room temperature and increase the temperature to about 50 C. and keep it there for one to two hours. The mixture will become brown. Cool and add to it 300 cc. of 95% alcohol containing 0.45 of a mole of solid potassium hydroxide. The mixture will heat up but do not allow the temperature to exceed the boiling point of the alcohol. Keep it at this temperature with nitrogen passing through the solution for two to three hours, then remove most of the alcohol under reduced pressure. Cool and dilute the mixture with about four volumes of cold deoxygenated water and separate the resulting layers. Extract the aqueous layer once or twice with petroleum ether and combine non-aqueous extracts. Extract the non-aqueous solutions with 5% aqueous tartaric acid solution. Finally, dry the non-aqueous solutions, remove the solvents under reduced pressure and subject the residue to a high vacuum at not higher than (50-80 C. (bath temperature) in order to remove volatile constituents.

Conversion of Compound VIethyl into 5- trans-Compound VIIIeth1/l (chemical method).-Compound VIethyl (3.3 g.) dissolved in about 25 cc. of anhydrous methanol was added to 100 cc. of 90% ethanol containing 5 g. of solid potassium hydroxide and to this mixture was added 0.8 g. of zinc dust. Gentle stirring was provided by nitrogen bubbling through the mixture for about 20 hours. The reaction mixture was then diluted with water and extracted with olefin-free petroleum ether, the latter dried and the petroleum ether removed. The residue was S-trans Compound VIII-ethyl.

Conversion of 5-trans Compound VIII-ethyl into 5 trans vitamin A ethyl ether.This conversion was accomplished either by dehydration using p-toluene sulfonic acid in boiling toluene, or by the dehydrobromination method described previously.

Compound IIethyl used in the preparation of the ethyl ether of vitamin A may be prepared as described in my application Serial No. 409,314.

Compound I may be prepared as described in my application Serial No. 353,775, filed August 22, 1940.

For the preparation of the trityl ether of vitamin A one starts with compound II phenyl, that is, Compound II in which the three R's stand for 8 phenyl groups, which may be prepared as described in my application Serial No. 409,314 instead of Compound II-ethyl as described above.

I claim: 1. As a new product a compound of the formula CH3/CH1 which comprises reactin a compound of the in which R stands for a member of the group consistingof hydrogen and hydrocarbon groups and X stands for a member of the group consisting of the Grignard group and metals of the first group of the periodic system with a compound of the formula I 5. Process as defined in claim 4 in which X stands for the Grignard group.

6. Process as defined in claim 4 in which X stands for a metal of the first group of the periodic system.

'7. Process as defined in claim 4 in which the product is dehydrated.

8. Process as defined in claim 4 in which the product is dehydrated and the resulting compound hydrogenated to convert the acetylene into an ethylene bond, the hydrogenation being effected catalytically.

9. Process as defined in claim 4 in which the product is dehydrated and the resulting compound hydrogenated to convert the acetylene into an ethylene bond, the hydrogenation being effected chemically.

10. Process as defined in claim 4 in which the product is hydrogenated catalytically.

11. Process as defined in claim 4 in which the product is partially and selectively hydrogenated chemically.

12. Asa new product a compound or the formula OH; on,

on3 on, R

in which R stands for a member or the group consisting of hydrogen and hydrocarbon groups.

NICHOLAS A. MILAS. 

